Abstract
Small insertions and deletions (indels) and large structural variations (SVs) are major contributors to human genetic diversity and disease. However, mutation rates and characteristics of de novo indels and SVs in the general population have remained largely unexplored. We report 332 validated de novo structural changes identified in whole genomes of 250 families, including complex indels, retrotransposon insertions, and interchromosomal events. These data indicate a mutation rate of 2.94 indels (1–20 bp) and 0.16 SVs (>20 bp) per generation. De novo structural changes affect on average 4.1 kbp of genomic sequence and 29 coding bases per generation, which is 91 and 52 times more nucleotides than de novo substitutions, respectively. This contrasts with the equal genomic footprint of inherited SVs and substitutions. An excess of structural changes originated on paternal haplotypes. Additionally, we observed a nonuniform distribution of de novo SVs across offspring. These results reveal the importance of different mutational mechanisms to changes in human genome structure across generations.
Genome of the Netherlands Consortium
Notes
[1] Supplementary material [Supplemental material is available for this article.]
[2] Article published online before print. Article, supplemental material, and publication date are at http://www.genome.org/cgi/doi/10.1101/gr.185041.114.
Notes
[3] Department of Genetics, University of Groningen, University Medical Center Groningen, Groningen 9700RB, The Netherlands
[4] Genomics Coordination Center, University of Groningen, University Medical Center Groningen, Groningen 9700RB, The Netherlands
[5] Netherlands Bioinformatics Centre, Nijmegen 6245 GA, The Netherlands
[6] Department of Medical Statistics and Bioinformatics, Leiden University Medical Center, Leiden 2300RC, The Netherlands
[7] Department of Human Genetics, Leiden University Medical Center, Leiden 2300RC, The Netherlands
[8] Department of Epidemiology, Erasmus Medical Center, Rotterdam 3000CA, The Netherlands
[9] Department of Biological Psychology, VU University Amsterdam, Amsterdam 1081BT, The Netherlands
[10] Legal Pathways Institute for Health and Bio Law, Aerdenhout, The Netherlands
[11] University Medical Center Groningen, Groningen 9700RB, The Netherlands
[12] BGI, Shenzhen 518083, China
[13] Leiden University, Leiden 2300RA, The Netherlands
[14] The Genome Institute, Washington University, St. Louis, Missouri 63108, USA
[15] Leiden University Medical Center, Leiden 2300RC, The Netherlands
[16] Department of Internal Medicine, Erasmus Medical Center, Rotterdam 3000CA, The Netherlands
[17] Department of Human Genetics, Radboud University Medical Center, Nijmegen 6525GA, The Netherlands
[18] Amsterdam Medical Center, Amsterdam 1105 AZ, The Netherlands
[19] Department of Genetics, Harvard Medical School, Boston, Massachusetts 02115, USA
[20] Broad Institute of Harvard and MIT, Cambridge, Massachusetts 02142, USA
[21] Department of Genome Sciences, University of Washington, Seattle, Washington 98105, USA
[22] Department of Medical Genetics, Center for Molecular Medicine, University Medical Center Utrecht, Utrecht 3584CG, The Netherlands
[23] European Research Institute for the Biology of Ageing, University of Groningen, University Medical Center Groningen, Groningen 9713AD, The Netherlands
[24] Department of Epidemiology, University Medical Center Utrecht, Utrecht 3584CG, The Netherlands